3-Substituted tetrahydropyridopyrimidinone derivatives, method for producing the same, and their use

ABSTRACT

3-substituted tetrahydropyridopyrimidinone derivatives of the formula (I) wherein the radicals have the meanings given in the Description, to a method for producing said derivatives and, to their use for producing active ingredients for drugs.

The invention relates to 3-substituted tetrahydropyrido-pyrimidinone derivatives, their preparation and use for producing active ingredients for drugs.

Classical antidepressants and the newer selective serotonin reuptake inhibitors (SSRIS) develop their antidepressant effect inter alia by inhibiting active reuptake of the transmitter into the presynaptic nerve endings. Unfortunately, the antidepressant effect thereof does not have its onset until treatment has lasted at least 3 weeks, and, moreover, about 30% of patients are therapy-resistant.

Blockade of presynaptic serotonin autoreceptors increases, by abolishing negative coupling, the serotonin release and thus the current transmitter concentration in the synaptic cleft. This increase in the transmitter concentration is regarded as the principle of the antidepressant effect. This mechanism of action differs from previously known antidepressants which activate both the presynaptic and somatodendritic autoreceptors and therefore result in a delayed onset of action, only after desensitization of these autoreceptors. Direct autoreceptor blockade bypasses this effect.

The derivatives described in JP 08027149 and JP 04054181 are known.

According to current knowledge, the presynaptic serotonin autoreceptor is of the 5-HT_(1B) subtype (Fink et al., Arch. Pharmacol. 352 (1995), 451). Selective blockade thereof by 5-HT_(1B/D) antagonists increases the serotonin release in the brain: G. W. Price et al., Behavioural Brain Research 73 (1996), 79-82; P. H. Hutson et al., Neuropharmacology Vol. 34, No. 4 (1995), 383-392.

However, surprisingly, the selective 5-HT_(1B) antagonist GR 127 935 reduces serotonin release in the cortex after systemic administration. One explanation might be stimulation of somatodendritic 5-HT_(1A) receptors in the graphed region by the released serotonin, which inhibits the firing rate of serotonergic neurons and thus serotonin release (M. Skingle et al., Neuropharmacology Vol. 34 No. 4 (1995), 377-382, 393-402).

One strategy for bypassing the autoinhibitory effects in serotonergic areas of origin thus aims at blockade of presynaptic 5-HT_(1B) receptors. This hypothesis is supported by the observation that the effect of paroxetine on serotonin release in the dorsal raphe nucleus of the rat is potentiated by the 5-HT_(1B) receptor antagonist GR 127 935 (Davidson and Stamford, Neuroscience Letts., 188 (1995), 41).

The second strategy includes blockade of both types of autoreceptors, namely the 5-HT_(1A) receptors, in order to intensify neuronal firing, and the 5-HT_(1B) receptors, in order to increase terminal serotonin release (Starkey and Skingle, Neuropharmacology 33 (3-4) (1994), 393).

5-HT_(1B/D) antagonists, alone or coupled to a 5-HT_(1A) receptor antagonistic component, should therefore cause a greater increase in serotonin release in the brain and might therefore be associated with advantages in the therapy of depressions and related psychological disorders.

It has now been found that 3-substituted tetrahydropyrido-pyrimidinone derivatives of the formula I

where

one of the two radicals X and Y is CH₂ and the other is NR¹, R¹ is hydrogen, (C₁₋₆) alkyl branched or unbranched, CO—(C₁₋₄)-alkyl, CO₂tBu, CO-aryl and a phenylalkyl-C₁-C₄ radical which in turn may be substituted on the aromatic system by F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro,

A is branched or unbranched (C₁₋₁₀)-alkylene or straight-chain or branched (C₂₋₁₀)-alkylene which comprises at least one group Z which is selected from 0, S, NR², cyclopropyl, CHOH, a double or triple bond,

R² is hydrogen and C₁-C₄ alkyl,

B is 4-piperidine, 4-tetrahydro-1,2,3,6 pyridine, 4-piperazine or the corresponding cyclic compounds enlarged by one methylene group, with the linkage to A being via an N atom of B, and

Ar is phenyl which is unsubstituted or substituted by (C₁₋₆) alkyl branched or unbranched, O—(C₁₋₆) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR² ₂, CO₂R², cyano or phenyl, or is tetralin, indan, fused aromatic systems such as naphthalene which is unsubstituted or substituted by (C₁₋₄)-alkyl or O(C₁₋₄)-alkyl, anthracene or 5- or 6-membered aromatic heterocycles having 1 or 2 heteroatoms which are selected, independently of one another, from O and N, which may be fused to other aromatic radicals,

and their salts with physiologically tolerated acids, have valuable pharmacological properties.

Particularly preferred compounds are those where

one of the two radicals X and Y is CH₂ and the other is NR¹,

R¹ is hydrogen, (C₁₋₄)-alkyl branched or unbranched, CO—(C₁₋₄)-alkyl, CO₂tBu, COPh or a phenylalkyl C₁-C₂ radical which in turn can be substituted on the aromatic system by F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, hydroxyl or cyano,

A is (C₂₋₅) alkylene branched or unbranched or (C₂₋₅)-alkylene which comprises a group Z which is selected from CHOH, cyclopropyl, a double or a triple bond,

B is 4-piperidine, 4-tetrahydro-1,2,3,6 pyridine, 4-piperazine or homopiperazine, where the linkage to A takes place via an N atom of B, and

Ar is phenyl which is unsubstituted or substituted by (C₁₋₆)-alkyl branched or unbranched, O—(C₁₆)-alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, CO₂R², NR² ₂, cyano or phenyl, or is tetralin, indan, fused aromatic systems such as naphthalene which is unsubstituted or substituted by (C₁₋₄) alkyl or O(C₁₋₄) alkyl, or 5- or 6-membered aromatic heterocycles having 1 or 2 nitrogen atoms, which may be fused to other aromatic radicals.

Particularly preferred compounds of the formula I are those listed in claim 3.

The compounds of the formula I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The invention also includes the respective tautomeric forms.

The novel compounds of the formula I can be prepared by reacting a compound of the formula II

where A, X and Y have the abovementioned meanings, and Q is a group which can be eliminated (eg. Cl, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a compound of the formula III,

H—B—Ar  (III),

where B and Ar have the abovementioned meanings, in a manner known per se, and converting the compound obtained in this way where appropriate into the addition salt with a physiologically tolerated acid. It is likewise possible to react a compound of the formula IV

with a compound of the formula V

 Q—A—B—Ar  (V)

in a manner known per se.

Another variant of the synthesis comprises linking a compound of the formula VI

with a compound of the formula III by a reductive amination known per se.

Compounds of the formula III can be synthesized by

1. Linking compounds of the formula VII

W—B¹  (VII)

 where B¹ is piperazine or homopiperazine and W is hydrogen or one of the usual amino protective groups (eg. Boc or Cbz), with a compound of the formula VIII

P—Ar  (VIII),

 where P is B(OH)₂, SnR₃, OTf, Br, Cl, or I, and R is C₁-C₄-alkyl, in a known manner; or

2. linking compounds of the formula IX

W—B²—p¹  (IX),

 where B² is 4-tetrahydro-1,2,3,6-pyridine and the corresponding cyclic compounds enlarged by one methylene group, and P¹ is Cl, Br, I, SnR₃, where R is C₁-C₄-alkyl, or OTf, with a compound of the formula X

 P—Ar  (X),

 where W, P and Ar each have the abovementioned meanings, and the reactions take place by known processes as described, for example, in

S. L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215,

J. F. Hartwig et al. Tetrahedron Lett. 1995, 36, 3604

J. K. Stille et al. Angew. Chem. 1986, 98, 504,

S. L. Buchwald et al. Angew. Chem. 1995, 107, 1456 or

J. F. Hartwig et al. J. Am. Chem. Soc 1996, 118, 7217 or

J. F. Hartwig et al. J. Org. Chem. 1997, 62, 1268,

S. L. Buchwald et al. J. Org. Chem. 1997, 62, 1264 and the literature cited therein or

S. L. Buchwald et al J. Am. Chem. Soc 1997, 119, 6054,

J. K. Stille, Angew. Chem. 1986, 98, 504 or

J. K. Stille et al. J.Org. Chem. 1990, 55, 3014,

M. Pereyre et al. “Tin in Organic Synthesis”, Butterworth 1987; or

3. reducing compounds of the formula (XI)

W—B²—Ar  (XI),

 where B² has the abovementioned meaning, to compounds of the formula XII

W—B³—Ar  (XII),

 where B³ is piperidines linked in the 1,4 positions, and the corresponding ring compounds enlarged by one methylene group; or

4. cyclizing compounds of the formula XIII

W—N—(C₂H₄Q)₂  (XIII),

 where W and Q have the meanings described above, with a compound of the formula XIV

NH₂—Ar  (XIV),

 where Ar has the abovementioned meaning, to give compounds of the formula XV

W—B¹—Ar  (XV).

The substances of the formulae III and V which are required as starting materials for synthesizing the novel compounds are known or can be synthesized by known processes (eg. Organikum Barth Dt. Verl. der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press) from analogous precursors.

Further reaction of the compounds

H—B—Ar  (III)

prepared as in 1. to 4., with subsequent elimination of any protective groups, to give compounds of the formula V takes place by linkage with compounds of the formula XVI

Q—A—Q′  (XVI),

where Q and Q′ are leaving groups, under conditions known per se.

The substances of the formula II, IV, VI and of the formula P—Ar, NH₂—Ar, W—B¹ and W—B²—P¹ required as starting materials for synthesizing the novel compounds are known or can be synthesized from similar precursors by methods described in the literature (eg. B. Dumaitre, N. Dodic J. Med. Chem. 1996, 39, 1635 or A. Yokoo et al. Bull. Chem. Soc. Jpn. 1956, 29, 631 or L. Börjeson et al. Acta Chem. Chem. [sic] 1991, 45, 621 or Organikum Barth Dt. Verl. der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley & Sons Inc. NY and the literature cited in each of these).

The reactions described above generally take place in an inert organic solvent, eg. dimethylformamide, acetonitrile, dichloromethane, dimethyl sulfoxide, dimethoxyethane, toluene, ethyl acetate, xylene, a ketone such as acetone or methyl ethyl ketone, an alcohol such as ethanol or n-butanol, or a cyclic saturated ether, eg. tetrahydrofuran or dioxane.

The reactions generally take place at from 20° C. to the boiling point of the solvent and are generally complete within 1 to 20 hours. If required, they take place in the presence of an acid-binding agent such as sodium or potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, organometallic compounds (butyllithium, alkylmagnesium compounds), potassium t-butoxide, pyridine or triethylamine.

Where appropriate, the reactions take place with use of a catalyst such as transition metals and their complexes, eg. Pd-C, Pd(PPh₃)₄, Pd(OAc)₂, Pd(P(oTol)₃)₄, Pd₂(dba)₃ or Ni(COD)₂.

The crude product is isolated in a conventional way, for example by filtration, removal of the solvent by distillation or extraction from the reaction mixture.

The novel compounds of the formula I can be purified either by recrystallization from conventional organic solvent or by column chromatography.

Besides the 3-substituted tetrahydropyridopyrimidinone derivatives, the invention also comprises the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Further acids which can be used are described in “Fortschritte der Arzneimittelforschung”, Volume 10, pages 224 et seq., Birkhäuser Verlag, Basle and Stuttgart, 1966.

The acid addition salts are prepared in a conventional way by mixing the free base with the appropriate acid, where appropriate in solution in an organic solvent, eg. a lower alcohol such as methanol, ethanol or propanol, an ether such as methyl t-butyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate.

The invention accordingly also relates to a therapeutic composition which comprises a compound of the formula I or its pharmacologically suitable acid addition salt as active ingredient in addition to conventional carriers and diluents, and to the use of the novel compounds for controlling diseases.

The novel compounds can be administered orally or parenterally, intravenously or intramuscularly, in a conventional way.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient is about 1-100 mg/kg of body weight on oral administration and 0.1-10 mg/kg of body weight on parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film) coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et. al: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain from 1 to 99% by weight of active ingredient.

The novel compounds have a high affinity for 5-HT_(1B), 5-HT_(1D) and 5-HT_(1A) serotonin receptors. Approximately the same degree of affinity, at least of the same order of magnitude, is shown for these receptors. In addition, some of the novel compounds show good inhibition of serotonin reuptake, a principle which is implemented in most antidepressants.

These compounds are suitable as drugs for treating pathological states in which the serotonin concentration is reduced and in which it is wished for therapeutic purposes to block specifically the activity of the presynaptic 5-HT_(1B), 5-HT_(1A), 5-HT_(1D) receptors without having a great effect on other receptors. An example of such a pathological state is depression.

The compounds of the present invention can also be of use for treating mood disturbances with a central nervous causation, such as seasonal affective disorders and dysthymia. These also include anxiety states such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive neuroses and post-traumatic stress symptoms, memory disturbances including dementia, amnesias and age-related loss of memory, and psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.

The novel compounds can additionally be used to treat endocrine disorders such as hyperprolactinemia and to treat vasospasms (especially of the cerebral vessels), hypertension and gastrointestinal disorders associated with disturbances of motility and secretion. Another area of use comprises sexual disorders.

The following examples serve to illustrate the invention without restricting it.

EXAMPLE 1 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4(3H)-one

Preparation of the starting materials

a) 5,6,7,8-Tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4(3H)-one

4.7 g of sodium were ,a little at a time, allowed to react in 250 ml of ethanol, and a suspension of 14.2 g (0.05 mol) of methyl N-benzyl-4-piperidone-3-carboxylate in ethanol was then added dropwise at 5-10° C. The mixture was stirred for 30 minutes, after which 6 g (0.075 mol) of formamidine hydrochloride were added slowly, and the reaction mixture was heated under reflux for 10 h. The solvent was removed under reduced pressure and the residue was taken up in 100 ml of water and adjusted to pH=6.5-7 with 2N hydrochloric acid, so that the product precipitated out. The crystals were filtered off with suction and dried in a vacuum drying cabinet, and 8 g (66%). Melting point 88° C. 5,6,7,8-Tetrahydro-7-benzylpyrido[3,4-d] pyrimidin-4(3H)-one (melting point 199° C.) and methyl 5,6,7,8-tetrahydropyrido[4,3-d] pyrimidin-4(3H)-one-6-carboxylate (melting point 160° C.) were obtained similarly.

b) 1-(2-methoxyphenyl)-4-(2-chloroeth-l-yl) piperazine

At room temperature, a solution of 19.2 g (0.1 mol) of o-methoxyphenylpiperazine and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of DMF was initially charged and, after 30 min, 30 ml (0.36 mol) of 1-bromo-2-chloroethane were added. The mixture was stirred at room temperature for 2 h. The mixture was poured into ice-water then extracted with methyl tert-butyl ether, and the organic phases were washed with water, dried with sodium sulfate and subsequently concentrated. The residue was dissolved in ethyl acetate and the hydrochloride was precipitated out by addition of 30% strength isopropanol/HCI solution, filtered off with suction and dried at 40° C. in a vacuum drying oven. This gave 17 g (67%) of substance. Melting point 200° C.

1-(2-Methoxyphenyl)-4-(3-chloroprop-1-yl)piperazine (melting point 217° C., hydrochloride), 1-(3,4-methylphenyl)-4-(2-chloroeth-1-yl) piperazine (melting point 260° C., hydrochloride), 1-(2-pyrimidyl)-4-(2-chloroeth-1-yl) piperazine (melting point 270° C., hydrochloride), 1-(naphth-1-yl)-4-(3-chloroprop-1-yl)piperazine (melting point 217° C., hydrochloride), were obtained in a similar manner.

Two exemplary syntheses for preparing the piperazines are shown below. 1-Tetralin-5-yl-piperazine

14.7 g (0.1 mol) of 5-aminotetralin and 18 g (0.11 mol) of bis(β-chloroethyl)amine hydrochloride in 300 ml of n-butanol were refluxed for 48 h, 5.4 g of sodium carbonate were added after cooling and the mixture was once more refluxed for 20 h. The precipitate which was formed by cooling was filtered off with suction, and taken up in water and admixed with 2N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. In this manner, it is possible to isolatel0.7 g (50%) of the product as an oil.

4-Piperazin-1-ylisoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of tris(dibenzylideneacetone) dipalladium, 0.11 g (0.18 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-dinaphthyl and 2.92 g (30.4 mmol) of sodium t-butoxide were admixed in 50 ml of toluene and stirred at 75° C. for 2 h. The reaction mixture was poured onto ice/sodium chloride and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed using a rotary evaporator. The product crystallized out, and it was filtered off with suction and washed with pentane. This gave 5.5 g (81%) of the Boc-protected piperazine (melting point 111° C.). 5.2 g (16.6 mmol) of this substance were taken up in 17 ml of dichloromethane and, at 0° C., slowly admixed with 17 ml (0.22 mol) of trifluoroacetic acid. The mixture was stirred at 0° C. for 4 h, poured into ice-water and extracted with dichloromethane. The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and substantial removal of the solvent the residue was diluted with diethyl ether and the hydrochloride was precipitated out using ethereal hydrochloric acid. This gave 3.2 g (67%) of the product. (Melting point 293° C.).

The following compounds were prepared similarly to the two processes described: 1-naphth-1-ylazepane (85° C., hydrochloride), 1-naphth-1-ylmethylpiperazine (oil), 4-piperazin-1-yl-indane (oil), 1-naphth-1-ylpiperazine (82° C.), 4-piperazin-1-ylquinazoline (205° C., decomposition) and 4-piperazin-1-ylquinazoline (320° C., hydrochloride). Other derivatives were commercially available.

Preparation of the end product

2.9 g (10 mmol) of chloroethylpiperazine and 2.8 g (20 mmol) of potassium carbonate were added to a solution of 2.4 g (10 mmol) of tetrahydropyridopyrimidine in 40 ml of DMF. After reaction at 90° C. for two hours, and then poured onto ice-water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent was removed under reduced pressure. The oil that remained was taken up in acetone, and the hydrochloride was precipitated out using isopropanol/HCI. This gave 4 g (75%) of the product were obtained (melting point 205° C.).

NMR: CDCI₃8.0 (s, 1H), 7.4-7.2 (m, 5H), 7.1-6.8 (m, 4H), 4.0 (t, 2H), 3.8 (s, 3H, 3.7 (s, 2H), 3.5 (s, 2H), 3.1 (brd. s, 4H), 2.8-2.6 (m, 10H) ppm.

The following compounds were obtained in a similar way:

EXAMPLE 2

3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-7-benzylpyrido[3,4-d]pyrimidin-4(3H)-one (melting point 181° C., hydrochloride).

EXAMPLE 3

3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4(3H)-one (melting point 198° C., hydrochloride).

EXAMPLE 4

3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl-5,6,7,8-tetrahydro-7-benzylpyrido[3,4-d]pyrimidin-4(3H)-one (melting point 190° C., hydrochloride).

EXAMPLE 5

3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]2-hydroxypropyl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(3H)-one.

EXAMPLE 6

t-butyl 3-[4-naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one-6-carboxylate (melting point 170° C., hydrochloride).

EXAMPLE 7

3-[2-[4-naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-(3H)-one (melting point 268° C., hydrochloride).

EXAMPLE 8

3-[2-[4-(naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one (melting point 272° C., hydrochloride).

EXAMPLE 9

3-[2-[4-(quinazolin-4-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4-(3H)-one (melting point 258° C., hydrochloride).

EXAMPLE 10

3-[2-[4-naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(3H)-one (melting point 227° C., hydrochloride).

EXAMPLE 11

3-[2-[4-(naphth-1-yl)-tetrahydro-1,2,3,6-pyridin-1-yl]eth-l-yl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(3H)-one (melting point 216° C., hydrochloride).

Synthesis of the starting materials

a) N-Boc-4-(trifluoromethanesulfonyloxy)-1,2,3,6-tetrahydropyridine

At −78° C., a solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF was deprotonated using 100 mol of nBuLi (1.6M in hexane), and, after 30 minutes at this temperature, 20.0 g (0.1 mol) of N-Boc-piperid-4-one dissolved in 50 ml of THF were added dropwise. After a further three hours at −78° C., a solution of 39.3 g (0.11 mol) of N,N,-bistrifluoromethanesulfonylaniline in 50 ml of THF was added, and the mixture was allowed to warm to room temperature overnight. For work-up, the mixture was admixed with water and extracted with ether, the organic phases were washed with NaHCO₃ solution and water and dried over sodium sulfate, and the solvent was concentrated. The crude product was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate=3/1).

Yield: 20.2 g (60% of theory) 1H-NMR:(270 MHz,CDCl₃)δ=1.4 (s, 9H); 2.4(m, 2H); 3.6 (t, 2H); 4.1 (m, 2H); 5.8 (m, 1H)ppm

b) N-Boc-4-naph-1-yltetrahydro-1,2,3,6-pyridine

22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of naphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium chloride, 0.85 g (4.44 mmol) of copper(l) iodide and 2.1 g (1.77 mmol) of tetrakistriphenylphosphinepalladium were added successively to 14.7 g (44.4 mmol) of the compound described above dissolved in 115 ml of dimethoxyethane, and the mixture was boiled for 4 h. For work-up, aqueous ammonia solution was added and the mixture was extracted with water and ethyl acetate, the extract was dried over sodium sulfate and the residue which was obtained after evaporation of the solvent, was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate=4/1).

Yield: 8.2 g (57% of theory) 1H-NMR (270 MHz, CDCI₃): δ=1.4 (s, 9H); 2.5 (m, 2H); 3.7(t, 2H); 4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5(m, 3H); 7.3-8.0 (m, 3H) ppm.

c) 4-Naphth-1-yltetrahydro-1,2,3,6-pyridine

7.84 g (25.3 mmol) of N-Boc-4-naphth-1-yltetrahydro-1,2,3,6-pyridine were stirred overnight at room temperature with 200 ml of ethereal hydrochloric acid, and the precipitated product was filtered off and dried.

Yield: 5.5 g (88% of theory).

d) Preparation of the end compound

0.51 g (2 mmol) of 4-maphth-1-yltetrahydro-1,2,3,6-pyridine dissolved in ml of dry DMF was admixed with 0.61 g (2 mmol) of 3-(2-chloroeth-l-yl)-3, 5,7,8-tetrehydro-4-oxo-6-benzylpyrido [4,3-d]pyrimidine and with 2 ml (17 mmol) of thiethylamine, and the mixture was stirred at 120° C. for 5 h. The organic phase was diluted with ether, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified chromotographically, giving a white solid by precipitating the salt using ethereal hydrochloric acid solution.

Yield: 0.2 g (20% of theory) Melting point: 237° C.

EXAMPLE 12

3-[2-[4-(Naphth-1-yl)piperidin-1-yl]eth-1-yl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(3H)-one

4-Naphth-1-ylpiperidine

3.7 g (15.3 mmol) of 4-naphth-1-yltetrahydro-1,2,3,6-pyridine dissolved in methanol, were hydrogenated at room temperature with hydrogen for 48 h, with addition of 0.8 g of palladium on carbon. The catalyst was filtered off, and the solvent was concentrated.

Yield: 1.8 g (56% of theory) 1H-NMR (270 MHz, CDCl₃)δ=1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt, 2H); 3.3 (d, 2H; 3.5 (tt, 1H); 7.4-7.6 (m, 4H); 7.7 (d, 1H); 7.9 (d, 1H); 8.1 (d, 1H) ppm.

Preparation of the end product

0.42 g(2mmol) of 4-naphtha-1-ylpiperidine, dissolved in 30 ml of dry DMF, was admixed with 0.61 g (2 mmol) of 3-(2-chloroeth-1-yl)-3.5.7.8-tetrahidro-4-oxo-6-benzylpyrido [4,3d] pyrimidine and with 2 ml (17 mmol) of triethylamine, and the mixture was stirred at 120° C. for 5 h. The organic phase was diluted with ether, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified chromatographically, giving a white solid by precipitating the salt using ethereal hydrochloric acid solution.

Yield: 0.24 g (27% of theory) 1H-NMR (270 MHz, CDCl₃)δ=8.3 (s, 1H), 8.0 (d,1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.5-7.2 (m, 9H), 4.5 (s, 2H), 4.0 (s, 2H), 3.7-2.3 (m, 15H), 2.1 (d, 2H) ppm.

Other preferred compounds of the formula I according to the invention are listed in the table below.

M.p. hydro- No. X Y R¹ A R² B Ar chloride 13. NR¹ CH₂ H C₂ 1,4-piperazinylene Ph 14. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-OH—Ph 15. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-OMe—Ph 16. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-Me—Ph 17. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-CN—Ph 18. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-Cl—Ph 19. NR¹ CH₂ H C₂ Me 1,4-piperazinylene 3-NR² ₂—Ph 20. NR¹ CH₂ H C₂ Me 1,4-piperazinylene 3-CO₂R²—Ph 21. NR¹ CH₂ H C₂ 1,4-piperazinylene 3-CF₃—Ph 22. NR¹ CH₂ H C₂ 1,4-piperazinylene 3-NO₂—Ph 23. NR¹ CH₂ H C₂ 1,4-piperazinylene 3-F—Ph 24. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-iC₃—Ph 25. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-I—Ph 26. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-Br—Ph 27. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-O(n-C₄)—Ph 28. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-t-Bn—Ph 29. NR¹ CH₂ H C₂ H 1,4-piperazinylene 4-CO₂R²—Ph 30. NR¹ CH₂ H C₂ n-C₃ 1,4-piperazinylene 4-NR² ₂—Ph 31. NR¹ CH₂ H C₂ 1,4-piperazinylene 3-Me, 4-Me—Ph 32. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-Cl, 4-NO₂—Ph 33. NR¹ CH₂ H C₂ 1,4-piperazinylene 3-tBu, 5-CF₃—Ph 34. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-OMe, 5-Ph—Ph 35. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-OMe, 5-Cl, 5-Me—Ph 36. NR¹ CH₂ H C₂ 1,4-piperazinylene 5-tetralinyl 37. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-indanyl 38. NR¹ CH₂ H C₂ 1,4-piperazinylene 1-naphthyl 39. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-OMe-1-naphthyl 40. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-Me-1-naphthyl 41. NR¹ CH₂ H C₂ 1,4-piperazinylene 8-OMe-1-naphthyl 42. NR¹ CH₂ H C₂ 1,4-piperazinylene 3-indolyl 43. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-quinazolinyl 44. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-quinazolinyl 45. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-quinoxalinyl 46. NR¹ CH₂ H C₂ 1,4-piperazinylene 1-phthalazinyl 47. NR¹ CH₂ H C₂ 1,4-piperazinylene 1-quinolinyl 48. NR¹ CH₂ H C₂ 1,4-piperazinylene 1-isoquinolinyl 49. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-isoquinolinyl 50. NR¹ CH₂ H C₂ 1,4-piperazinylene 7-benzofuranyl 51. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-pyrimidinyl 52. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-tBu, 4-CF₃-6-pyrimidinyl 53. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-pyridinyl 54. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-Ph-4-quinazolinyl 55. NR¹ CH₂ H C₂ 1,4-piperazinylene 5-chromanyl 56. NR¹ CH₂ H C₂ 1,4-piperazinylene 3-isoxazolyl 57. NR¹ CH₂ H C₂ 1,4-piperazinylene 7-OMe-1-naphthyl 58. NR¹ CH₂ H C₂ 1,4-piperazinylene 1-tetralinyl 59. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-Et-naphthyl 60. NR¹ CH₂ H C₂ 1,4-piperazinylene 2-quinolinyl 61. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene Ph 62. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-OH—Ph 63. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-OMe—Ph 64. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-Me—Ph 65. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-CN—Ph 66. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-Cl—Ph 67. NR¹ CH₂ CH₂—Ph C₂ Me 1,4-piperazinylene 3-NR² ₂—Ph 68. NR¹ CH₂ CH₂—Ph C₂ Me 1,4-piperazinylene 3-CO₂R²—Ph 69. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 3-CF₃—Ph 70. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 3-NO₂—Ph 71. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 3-F—Ph 72. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-iC₃—Ph 73. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-I—Ph 74. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-Br—Ph 75. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-O(n-C₄)—Ph 76. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-tBu—Ph 77. NR¹ CH₂ CH₂—Ph C₂ H 1,4-piperazinylene 4-CO₂R²—Ph 78. NR¹ CH₂ CH₂—Ph C₂ n-C₃ 1,4-piperazinylene 4-NR² ₂—Ph 79. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 3-Me, 4-Me—Ph 80. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-Cl, 4-NO₂—Ph 81. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 3-tBu, 5-CF₃—Ph 82. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-OMe, 5-Ph—Ph 83. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-OMe, 4-Cl, 5-MePh 84. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 5-tetralinyl 85. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-indanyl 86. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 1-naphthyl 87. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-OMe-1-naphthyl 88. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-Me-1-naphthyl 89. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 8-OMe-1-naphthyl 90. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 3-indolyl 91. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-quinazolinyl 92. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-quinazolinyl 93. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-quinoxalinyl 94. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 1-phthalazinyl 95. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-quinolinyl 96. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 1-isoquinolinyl 97. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 4-isoquinolinyl 98. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 7-benzofuranyl 99. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-pyrimidinyl 100. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-tBu, 4-CF₃-6-pyrimidinyl 101. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-pyridinyl 102. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-Ph-4-quinazolinyl 103. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 5-chromanyl 104. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 3-isoxazolyl 105. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 7-OMe-1-naphthyl 106. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 1-tetralinyl 107. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-Et-naphthyl 108. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperazinylene 2-quinolinyl 109. NR¹ CH₂ Me C₂ 1,4-piperazinylene Ph 110. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-OH—Ph 111. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-OMe—Ph 112. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-Me—Ph 113. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-CN—Ph 114. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-Cl—Ph 115. NR¹ CH₂ Me C₂ Me 1,4-piperazinylene 3-NR² ₂—Ph 116. NR¹ CH₂ Me C₂ Me 1,4-piperazinylene 3-CO₂R²—Ph 117. NR¹ CH₂ Me C₂ 1,4-piperazinylene 3-CF₃—Ph 118. NR¹ CH₂ Me C₂ 1,4-piperazinylene 3-NO₂—Ph 119. NR¹ CH₂ Me C₂ 1,4-piperazinylene 3-F—Ph 120. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-iC₃—Ph 121. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-I—Ph 122. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-Br—Ph 123. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-O(n-C₄)—Ph 124. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-tBu—Ph 125. NR¹ CH₂ Me C₂ H 1,4-piperazinylene 4-CO₂R²—Ph 126. NR¹ CH₂ Me C₂ n-C₃ 1,4-piperazinylene 4-NR² ₂—Ph 127. NR¹ CH₂ Me C₂ 1,4-piperazinylene 3-Me, 4-Me—Ph 128. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-Cl, 4-NO₂—Ph 129. NR¹ CH₂ Me C₂ 1,4-piperazinylene 3-tBn, 5-CF₃—Ph 130. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-Me, 5-Ph—Ph 131. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-OMe, 4-Cl, 5-MePh 132. NR¹ CH₂ Me C₂ 1,4-piperazinylene 5-tetralinyl 133. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-indanyl 134. NR¹ CH₂ Me C₂ 1,4-piperazinylene 1-naphthyl 135. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-OMe-1-naphthyl 136. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-Me-1-naphthyl 137. NR¹ CH₂ Me C₂ 1,4-piperazinylene 8-OMe-1-naphthyl 138. NR¹ CH₂ Me C₂ 1,4-piperazinylene 3-indolyl 139. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-quinazolinyl 140. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-quinazolinyl 141. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-quinoxalinyl 142. NR¹ CH₂ Me C₂ 1,4-piperazinylene 1-phthalazinyl 143. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-quinolinyl 144. NR¹ CH₂ Me C₂ 1,4-piperazinylene 1-isoquinolinyl 145. NR¹ CH₂ Me C₂ 1,4-piperazinylene 4-isoquinolinyl 146. NR¹ CH₂ Me C₂ 1,4-piperazinylene 7-benzofuranyl 147. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-pyrimidinyl 148. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-tBu, 4-CF₃-6-pyrimidinyl 149. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-pyridinyl 150. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-Ph-4-quinazolinyl 151. NR¹ CH₂ Me C₂ 1,4-piperazinylene 5-chromanyl 152. NR¹ CH₂ Me C₂ 1,4-piperazinylene 3-isoxazolyl 153. NR¹ CH₂ Me C₂ 1,4-piperazinylene 7-OMe-1-naphthyl 154. NR¹ CH₂ Me C₂ 1,4-piperazinylene 1-tetralinyl 155. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-Et-naphthyl 156. NR¹ CH₂ Me C₂ 1,4-piperazinylene 2-quinolinyl 157. NR¹ CH₂ Boc C₂ 1,4-piperazinylene Ph 158. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-OMe—Ph 159. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-Me—Ph 160. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-Cl—Ph 161. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 3-CN—Ph 162. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 4-F—Ph 163. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 3-tBu, 5-CF₃—Ph 164. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 5-tetralinyl 165. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 4-indanyl 166. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 1-naphthyl 167. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-OMe-naphthyl 168. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-Me-naphthyl 169. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 8-OMe-naphthyl 170. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 4-quinazolinyl 171. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-quinazolinyl 172. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 1-phthalazinyl 173. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 4-quinolinyl 174. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 4-isoquinolinyl 175. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-pyrimidinyl 176. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-tBu, 4-CF₃-6-pyrimidinyl 177. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 2-pyridinyl 178. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene Ph 179. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-OMe—Ph 180. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-Me—Ph 181. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-Cl—Ph 182. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 3-CN—Ph 183. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 4-F—Ph 184. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 3-tBu, 5-CF₃—Ph 185. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 5-tetralinyl 186. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 4-indanyl 187. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 1-naphthyl 188. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-OMe-naphthyl 189. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-Me-1-naphthyl 190. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 8-OMe-1-naphthyl 191. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 4-quinazolinyl 192. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-quinazolinyl 193. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 1-phthalazinyl 194. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 4-quinolinyl 195. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 1-isoquinoline 196. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-pyrimidinyl 197. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-tBu, 4-CF₃-6-pyrimidinyl 198. NR¹ CH₂ CH₃C═O C₂ 1,4-piperazinylene 2-pyridinyl 199. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene Ph 200. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-OMe—Ph 201. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-Me—Ph 202. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-Cl—Ph 203. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 3-CN—Ph 204. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 4-F—Ph 205. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 3-tBu,5-CF₃—Ph 206. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 5-tetralinyl 207. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 4-indanyl 208. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 1-naphthyl 209. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-OMe-1-naphthyl 210. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-Me-1-naphthyl 211. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 8-OMe-1-naphthyl 212. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 4-quinazolinyl 213. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-quinazolinyl 214. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 1-phthalazinyl 215. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 4-quinolinyl 216. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 4-isoquinolinyl 217. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-pyrimidinyl 218. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-tBu, 4-CF₃-pyrimidinyl 219. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 2-pyridinyl 220. NR¹ CH₂ i-C₃ C₂ 1,4-piperazinylene 1-naphthyl 221. NR¹ CH₂ C₂—Ph C₂ 1,4-piperazinylene 1-naphthyl 222. NR¹ CH₂ C₂—(2-OMe)Ph C₂ 1,4-piperazinylene 1-naphthyl 223. NR¹ CH₂ C₃—(4-Cl)Ph C₂ 1,4-piperazinylene 1-naphthyl 224. NR¹ CH₂ C₂—(2-CF₃)Ph C₂ 1,4-piperazinylene 1-naphthyl 225. NR¹ CH₂ H C₃ 1,4-piperazinylene 5-tetralinyl 226. NR¹ CH₂ H C₃ 1,4-piperazinylene 1-naphthyl 227. NR¹ CH₂ H C₃ 1,4-piperazinylene 2-OMe—Ph 228. NR¹ CH₂ H C₃ 1,4-piperazinylene 4-isoquinolinyl 229. NR¹ CH₂ H C₃ 1,4-piperazinylene 2-pyrimidinyl 230. NR¹ CH₂ H C₃ 1,4-piperazinylene 2-OMe-naphthyl 231. NR¹ CH₂ CH₂—Ph C₃ 1,4-piperazinylene 5-tetralinyl 232. NR¹ CH₂ CH₂—Ph C₃ 1,4-piperazinylene 1-naphthyl 233. NR¹ CH₂ CH₂—Ph C₃ 1,4-piperazinylene 2-OMe—Ph 234. NR¹ CH₂ CH₂—Ph C₃ 1,4-piperazinylene 4-isoquinolinyl 235. NR¹ CH₂ CH₂—Ph C₃ 1,4-piperazinylene 2-pyridinyl 236. NR¹ CH₂ CH₂—Ph C₃ 1,4-piperazinylene 4-indane 237. NR¹ CH₂ Me C₃ 1,4-piperazinylene 5-tetralinyl 238. NR¹ CH₂ Me C₃ 1,4-piperazinylene 1-naphthyl 239. NR¹ CH₂ Me C₃ 1,4-piperazinylene 2-OMe—Ph 240. NR¹ CH₂ Me C₃ 1,4-piperazinylene 4-isoquinolinyl 241. NR¹ CH₂ Me C₃ 1,4-piperazinylene 2-pyrimidinyl 242. NR¹ CH₂ Me C₃ 1,4-piperazinylene 2-OMe-naphthyl 243. NR¹ CH₂ Boc C₃ 1,4-piperazinylene 5-tetralinyl 244. NR¹ CH₂ Boc C₃ 1,4-piperazinylene 1-naphthyl 245. NR¹ CH₂ Boc C₃ 1,4-piperazinylene 2-OMe—Ph 246. NR¹ CH₂ Boc C₃ 1,4-piperazinylene 4-isoquinolinyl 247. NR¹ CH₂ Boc C₃ 1,4-piperazinylene 2-pyrimidinyl 248. NR¹ CH₂ Boc C₃ 1,4-piperazinylene 2-OMe-naphthyl 249. NR¹ CH₂ CH₃—C═O C₃ 1,4-piperazinylene 5-tetralinyl 250. NR¹ CH₂ CH₃—C═O C₃ 1,4-piperazinylene 1-naphthyl 251. NR¹ CH₂ CH₃—C═O C₃ 1,4-piperazinylene 2-OMe—Ph 252. NR¹ CH₂ CH₃—C═O C₃ 1,4-piperazinylene 4-isoquinolinyl 253. NR¹ CH₂ CH₃—C═O C₃ 1,4-piperazinylene 2-pyrimidinyl 254. NR¹ CH₂ Ph—C═O C₃ 1,4-piperazinylene 2-OMe-naphthyl 255. NR¹ CH₂ Ph—C═O C₃ 1,4-piperazinylene 5-tetralinyl 256. NR¹ CH₂ Ph—C═O C₃ 1,4-piperazinylene 1-naphthyl 257. NR¹ CH₂ Ph—C═O C₃ 1,4-piperazinylene 2-OMe—Ph 258. NR¹ CH₂ Ph—C═O C₃ 1,4-piperazinylene 4-isoquinolinyl 259. NR¹ CH₂ Ph—C═O C₃ 1,4-piperazinylene 2-pyrimidinyl 260. NR¹ CH₂ Ph—C═O C₃ 1,4-piperazinylene 2-OMe-naphthyl 261. NR¹ CH₂ H C₂ 1,4-piperadinylene 5-tetralinyl 262. NR¹ CH₂ H C₂ 1,4-piperadinylene 1-naphthyl 263. NR¹ CH₂ H C₂ 1,4-piperidinylene 2-OMe—Ph 264. NR¹ CH₂ H C₂ 1,4-piperidinylene 4-isoquinolinyl 265. NR¹ CH₂ H C₂ 1,4-piperidinylene 2-pyrimidinyl 266. NR¹ CH₂ H C₂ 1,4-piperidinylene 2-OMe-naphthyl 267. NR¹ CH₂ Me C₂ 1,4-piperidinylene 5-tetralinyl 268. NR¹ CH₂ Me C₂ 1,4-piperidinylene 1-naphthyl 269. NR¹ CH₂ Me C₂ 1,4-piperidinylene 2-OMe—Ph 270. NR¹ CH₂ Me C₂ 1,4-piperidinylene 4-isoquinolinyl 271. NR¹ CH₂ Me C₂ 1,4-piperidinylene 2-pyrimidinyl 272. NR¹ CH₂ Me C₂ 1,4-piperidinylene 2-OMe-naphthyl 273. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperidinylene 5-tetralinyl 274. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperidinylene 1-naphthyl 275. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperidinylene 2-OMe—Ph 276. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperidinylene 4-isoquinolinyl 277. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperidinylene 2-pyrimidinyl 278. NR¹ CH₂ CH₂—Ph C₂ 1,4-piperidinylene 2-OMe-naphthyl 279. NR¹ CH₂ CH₃C═O C₂ 1,4-piperidinylene 5-tetralinyl 280. NR¹ CH₂ CH₃C═O C₂ 1,4-piperidinylene 1-naphthyl 281. NR¹ CH₂ CH₃C═O C₂ 1,4-piperidinylene 2-OMe—Ph 282. NR¹ CH₂ CH₃C═O C₂ 1,4-piperidinylene 4-isoquinolinyl 283. NR¹ CH₂ CH₃C═O C₂ 1,4-piperidinylene 2-pyrimidinyl 284. NR¹ CH₂ CH₃C═O C₂ 1,4-piperidinylene 2-OMe-naphthyl 285. NR¹ CH₂ Boc C₂ 1,4-piperidinylene 5-tetralinyl 286. NR¹ CH₂ Boc C₂ 1,4-piperidinylene 1-naphthyl 287. NR¹ CH₂ Boc C₂ 1,4-piperidinylene 2-OMe—Ph 288. NR¹ CH₂ Boc C₂ 1,4-piperidinylene 4-isoquinolinyl 289. NR¹ CH₂ Boc C₂ 1,4-piperidinylene 2-pyrimidinyl 290. NR¹ CH₂ Boc C₂ 1,4-piperidinylene 2-OMe-naphthyl 291. NR¹ CH₂ Ph—C═O C₂ 1,4-piperidinylene 5-tetralinyl 292. NR¹ CH₂ Ph—C═O C₂ 1,4-piperidinylene 1-naphthyl 293. NR¹ CH₂ Ph—C═O C₂ 1,4-piperidinylene 2-OMe—Ph 294. NR¹ CH₂ Ph—C═O C₂ 1,4-piperidinylene 4-isoquinolinyl 295. NR¹ CH₂ Ph—C═O C₂ 1,4-piperidinylene 2-pyrimidinyl 296. NR¹ CH₂ Ph—C═O C₂ 1,4-piperidinylene 2-OMe-naphthyl 297. NR¹ CH₂ H C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 5-tetralinyl 298. NR¹ CH₂ H C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 299. NR¹ CH₂ H C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe—Ph 300. NR¹ CH₂ H C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 4-isoquinolinyl 301. NR¹ CH₂ H C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-pyrimidinyl 302. NR¹ CH₂ H C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe-naphthyl 303. NR¹ CH₂ Me C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 5-tetralinyl 304. NR¹ CH₂ Me C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 305. NR¹ CH₂ Me C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe—Ph 306. NR¹ CH₂ Me C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 4-isoquinolinyl 307. NR¹ CH₂ Me C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-pyrimidinyl 308. NR¹ CH₂ Me C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe-naphthyl 309. NR¹ CH₂ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene tetralinyl 310. NR¹ CH₂ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 311. NR¹ CH₂ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe—Ph 312. NR¹ CH₂ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 4-isoquinolinyl 313. NR¹ CH₂ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-pyrimidinyl 314. NR¹ CH₂ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe-naphthyl 315. NR¹ CH₂ Boc C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene tetralinyl 316. NR¹ CH₂ Boc C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 317. NR¹ CH₂ Boc C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe—Ph 318. NR¹ CH₂ Boc C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 4-isoquinolinyl 319. NR¹ CH₂ Boc C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-pyrimidinyl 320. NR¹ CH₂ Boc C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe-naphthyl 321. NR¹ CH₂ CH₃C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene tetralinyl 322. NR¹ CH₂ CH₃C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 323. NR¹ CH₂ CH₃C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe—Ph 324. NR¹ CH₂ CH₃C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 4-isoquinolinyl 325. NR¹ CH₂ CH₃C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-pyrimidinyl 326. NR¹ CH₂ CH₃C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe-naphthyl 327. NR¹ CH₂ Ph—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene tetralinyl 328. NR¹ CH₂ Ph—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 329. NR¹ CH₂ Ph—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe—Ph 330. NR¹ CH₂ Ph—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 4-isoquinolinyl 331. NR¹ CH₂ Ph—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-pyrimidinyl 332. NR¹ CH₂ Ph—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe-naphthyl 333. NR¹ CH₂ H C₂ 1,4-homopiperazinylene 1-naphthyl 334. NR¹ CH₂ H C₂ 1,4-homopiperazinylene 2-OMe—Ph 335. NR¹ CH₂ H C₂ 1,4-homopiperazinylene 2-OMe-1-naphthyl 336. NR¹ CH₂ H C₃ 1,4-homopiperazinylene 2-pyrimidinyl 337. NR¹ CH₂ Me C₂ 1,4-homopiperazinylene 1-naphthyl 338. NR¹ CH₂ Me C₂ 1,4-homopiperazinylene 2-OMe—Ph 339. NR¹ CH₂ CH₂—Ph C₂ 1,4-homopiperazinylene 1-naphthyl 340. NR¹ CH₂ CH₂—Ph C₂ 1,4-homopiperazinylene 2-OMe—Ph 341. NR¹ CH₂ Boc C₂ 1,4-homopiperazinylene 1-naphthyl 342. NR¹ CH₂ Boc C₂ 1,4-homopiperazinylene 2-OMe—Ph 343. NR¹ CH₂ Boc C₃ 1,4-homopiperazinylene 2-OMe-1-naphthyl 344. NR¹ CH₂ CH₃—C═O C₂ 1,4-homopiperazinylene 1-naphthyl 345. NR¹ CH₂ CH₃—C═O C₂ 1,4-homopiperazinylene 2-OMe—Ph 346. NR¹ CH₂ Ph—C═O C₂ 1,4-homopiperazinylene 1-naphthyl 347. NR¹ CH₂ Ph—C═O C₂ 1,4-homopiperazinylene 1-OMe—Ph 348. NR¹ CH₂ Ph—C═O C₂ 1,4-homopiperazinylene 2-pyrimidinyl 349. NR¹ CH₂ H C₂ 1,4-homopiperadinylene 1-naphthyl 350. NR¹ CH₂ H C₂ 1,4-homopiperadinylene 2-OMe—Ph 351. NR¹ CH₂ H C₂ 1,4-homopiperadinylene 2-OMe-1-naphthyl 352. NR¹ CH₂ H C₃ 1,4-homopiperadinylene 2-pyrimidinyl 353. NR¹ CH₂ Me C₂ 1,4-homopiperidinylene 1-naphthyl 354. NR¹ CH₂ Me C₂ 1,4-homopiperidinylene 2-OMe—Ph 355. NR¹ CH₂ CH₂—Ph C₂ 1,4-homopiperidinylene 1-naphthyl 356. NR¹ CH₂ CH₂—Ph C₂ 1,4-homopiperidinylene 2-OMe—Ph 357. NR¹ CH₂ Boc C₂ 1,4-homopiperidinylene 1-naphthyl 358. NR¹ CH₂ Boc C₂ 1,4-homopiperidinylene 2-OMe—Ph 359. NR¹ CH₂ Boc C₃ 1,4-homopiperidinylene 2-OMe-1-naphthyl 360. NR¹ CH₂ CH₃—C═O C₂ 1,4-homopiperidinylene 1-naphthyl 361. NR¹ CH₂ CH₃—C═O C₂ 1,4-homopiperidinylene 2-OMe—Ph 362. NR¹ CH₂ Ph—C═O C₂ 1,4-homopiperidinylene 1-naphthyl 363. NR¹ CH₂ Ph—C═O C₂ 1,4-homopiperidinylene 2-OMe—Ph 364. NR¹ CH₂ Ph—C═O C₂ 1,4-homopiperidinylene 2-pyrimidinyl 365. NR¹ CH₂ H C₂ tetrahydro-2H-azepinylene 1-naphthyl 366. NR¹ CH₂ H C₂ tetrahydro-2H-azepinylene 2-OMe—Ph 367. NR¹ CH₂ H C₂ tetrahydro-2H-azepinylene 2-OMe-1-naphthyl 368. NR¹ CH₂ H C₃ tetrahydro-2H-azepinylene 2-pyrimidinyl 369. NR¹ CH₂ Me C₂ tetrahydro-2H-azepinylene 1-naphthyl 370. NR¹ CH₂ H C₂ tetrahydro-2H-azepinylene 2-OMe—Ph 371. NR¹ CH₂ CH₂—Ph C₂ tetrahydro-2H-azepinylene 1-naphthyl 372. NR¹ CH₂ CH₂—Ph C₂ tetrahydro-2H-azepinylene 2-OMe—Ph 373. NR¹ CH₂ Boc C₂ tetrahydro-2H-azepinylene 1-naphthyl 374. NR¹ CH₂ Boc C₂ tetrahydro-2H-azepinylene 2-OMe—Ph 375. NR¹ CH₂ Boc C₃ tetrahydro-2H-azepinylene 2-OMe-1-naphthyl 376. NR¹ CH₂ CH₃—C═O C₂ tetrahydro-2H-azepinylene 1-naphthyl 377. NR¹ CH₂ CH₃—C═O C₂ tetrahydro-2H-azepinylene 2-OMe—Ph 378. NR¹ CH₂ Ph—C═O C₂ tetrahydro-2H-azepinylene 1-naphthyl 379. NR¹ CH₂ Ph—C═O C₂ tetrahydro-2H-azepinylene 2-OMe—Ph 380. NR¹ CH₂ Ph—C═O C₂ tetrahydro-2H-azepinylene 2-pyrimidinyl 381. NR¹ CH₂ H CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 2-OMe—Ph 382. NR¹ CH₂ H CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 383. NR¹ CH₂ H CH₂—C(CH₂)—CH₂ 1,4-piperidinylene 1-naphthyl 384. NR¹ CH₂ Me CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 2-OMe—Ph 385. NR¹ CH₂ Me CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 386. NR¹ CH₂ Me CH₂—C(CH₂)—CH₂ 1,4-homopiperazinylene 1-naphthyl 387. NR¹ CH₂ CH₂—Ph CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 2-OMe—Ph 388. NR¹ CH₂ CH₂—Ph CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 389. NR¹ CH₂ CH₂—Ph CH₂—C(CH₂)—CH₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 390. NR¹ CH₂ Boc CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 2-OMe—Ph 391. NR¹ CH₂ Boc CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 392. NR¹ CH₂ Boc CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 2-pyrimidinyl 393. NR¹ CH₂ CH₂—C═O CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 2-OMe—Ph 394. NR¹ CH₂ CH₂—C═O CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 395. NR¹ CH₂ Ph—C═O CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 2-OMe—Ph 396. NR¹ CH₂ Ph—C═O CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 397. NR¹ CH₂ H CH₂—C(OH)—CH₂ 1,4-piperazinylene 2-OMe—Ph 398. NR¹ CH₂ H CH₂—C(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 399. NR¹ CH₂ H CH₂—C(OH)—CH₂ 1,4-piperidinylene 1-naphthyl 400. NR¹ CH₂ Me CH₂—C(OH)—CH₂ 1,4-piperazinylene 2-OMe—Ph 401. NR¹ CH₂ H CH₂—C(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 402. NR¹ CH₂ H CH₂—C(OH)—CH₂ 1,4-homopiperazinylene 1-naphthyl 403. NR¹ CH₂ CH₂—Ph CH₂—C(OH)—CH₂ 1,4-piperazinylene 2-OMe—Ph 404. NR¹ CH₂ CH₂—Ph CH₂—C(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 405. NR¹ CH₂ CH₂—Ph CH₂—C(OH)—CH₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 406. NR¹ CH₂ CH₂—Ph CH₂—C(OH)—CH₂ 1,4-piperazinylene 2-OMe—Ph 407. NR¹ CH₂ Boc CH₂—C(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 408. NR¹ CH₂ Boc CH₂—C(OH)—CH₂ 1,4-piperazinylene 2-pyrimidinyl 409. NR¹ CH₂ CH₃—C═O CH₂—C(OH)—CH₂ 1,4-piperazinylene 2-OMe—Ph 410. NR¹ CH₂ CH₃—C═O CH₂—C(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 411. NR¹ CH₂ Ph—C═O CH₂—C(OH)—CH₂ 1,4-piperazinylene 2-OMe—Ph 412. NR¹ CH₂ Ph—C═O CH₂—C(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 413. NR¹ CH₂ H C₂—N(Me)—C₂ 1,4-piperazinylene 2-OMe—Ph 414. NR¹ CH₂ H C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 415. NR¹ CH₂ H C₂—N(Me)—C₂ 1,4-piperidinylene 1-naphthyl 416. NR¹ CH₂ Me C₂—N(Me)—C₂ 1,4-piperazinylene 2-OMe—Ph 417. NR¹ CH₂ Me C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 418. NR¹ CH₂ Me C₂—N(Me)—C₂ 1,4-homopiperazinylene 1-naphthyl 419. NR¹ CH₂ CH₂—Ph C₂—N(Me)—C₂ 1,4-piperazinylene 2-OMe—Ph 420. NR¹ CH₂ CH₂—Ph C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 421. NR¹ CH₂ CH₂—Ph C₂—N(Me)—C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 422. NR¹ CH₂ Boc C₂—N(Me)—C₂ 1,4-piperazinylene 2-OMe—Ph 423. NR¹ CH₂ Boc C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 424. NR¹ CH₂ Boc C₂—N(Me)—C₂ 1,4-piperazinylene 2-pyrimidinyl 425. NR¹ CH₂ CH₃—C═O C₂—N(Me)—C₂ 1,4-piperazinylene 2-OMe—Ph 426. NR¹ CH₂ CH₃—C═O C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 427. NR¹ CH₂ Ph—C═O C₂—N(Me)—C₂ 1,4-piperazinylene 2-OMe—Ph 428. NR¹ CH₂ Ph—C═O C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 429. NR¹ CH₂ H CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 2-OMe—Ph 430. NR¹ CH₂ H CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 1-naphthyl 431. NR¹ CH₂ H CH₂—CH(CH₃)—CH₂ 1,4-piperadinylene 1-naphthyl 432. NR¹ CH₂ Me CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 2-OMe—Ph 433. NR¹ CH₂ Me CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 1-naphthyl 434. NR¹ CH₂ Me CH₂—CH(CH₃)—CH₂ 1,4-homopiperazinylene 1-naphthyl 435. NR¹ CH₂ CH₂—Ph CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 2-OMe—Ph 436. NR¹ CH₂ CH₂—Ph CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 1-naphthyl 437. NR¹ CH₂ CH₂—Ph CH₂—CH(CH₃)—CH₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 438. NR¹ CH₂ Boc CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 2-OMe—Ph 439. NR¹ CH₂ Boc CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 1-naphthyl 440. NR¹ CH₂ Boc CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 2-pyrimidinylene 441. NR¹ CH₂ CH₃—C═O CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 2-OMe—Ph 442. NR¹ CH₂ CH₃—C═O CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 1-naphthyl 443. NR¹ CH₂ Ph—C═O CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 2-OMe—Ph 444. NR¹ CH₂ Ph—C═O CH₂—CH(CH₃)—CH₂ 1,4-piperazinylene 1-naphthyl 445. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene Ph 446. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-OMe—Ph 447. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-Me—Ph 448. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-CN—Ph 449. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-Cl—Ph 450. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 3-CF₃—Ph 451. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 4-iC₃—Ph 452. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 3-Me, 4-Me—Ph 453. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 5-tetralinyl 454. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 4-indanyl 455. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 1-naphthyl 456. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-OMe-1-naphthyl 457. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-Me-1-naphthyl 458. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 8-OMe-1-naphthyl 459. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-quinazolinyl 460. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 1-phthalazinyl 461. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 4-quinolinyl 462. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 4-isoquinolinyl 463. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-pyrimidinyl 464. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperazinylene 2-pyridinyl 465. CH₂ NR¹ H C₂ 1,4-piperazinylene 2-OMe—Ph 466. CH₂ NR¹ H C₂ 1,4-piperazinylene 2-F—Ph 467. CH₂ NR¹ H C₂ 1,4-piperazinylene 3-tBu—Ph 468. CH₂ NR¹ H C₂ 1,4-piperazinylene 5-tetralinyl 469. CH₂ NR¹ H C₂ 1,4-piperazinylene 1-naphthyl 470. CH₂ NR¹ H C₂ 1,4-piperazinylene 2-OMe-1-naphthyl 471. CH₂ NR¹ H C₂ 1,4-piperazinylene 2-Me-1-naphthyl 472. CH₂ NR¹ H C₂ 1,4-piperazinylene 1-isoquinolinyl 473. CH₂ NR¹ H C₂ 1,4-piperazinylene 2-Ph-4-quinazolinyl 474. CH₂ NR¹ Me C₂ 1,4-piperazinylene 2-OMe—Ph 475. CH₂ NR¹ Me C₂ 1,4-piperazinylene 1-naphthyl 476. CH₂ NR¹ Me C₂ 1,4-piperazinylene 2-Me-1-naphthyl 477. CH₂ NR¹ Me C₂ 1,4-piperazinylene 2-pyrimidinyl 478. CH₂ NR¹ CH₃C═O C₂ 1,4-piperazinylene 2-OMe—Ph 479. CH₂ NR¹ CH₃C═O C₂ 1,4-piperazinylene 1-naphthyl 480. CH₂ NR¹ PhC═O C₂ 1,4-piperazinylene 2-OMe—Ph 481. CH₂ NR¹ PhC═O C₂ 1,4-piperazinylene 1-naphthyl 482. CH₂ NR¹ Boc C₂ 1,4-piperazinylene 2-OMe—Ph 483. CH₂ NR¹ Boc C₂ 1,4-piperazinylene 1-naphthyl 484. CH₂ NR¹ CH₂—Ph C₃ 1,4-piperazinylene 2-OMe—Ph 485. CH₂ NR¹ CH₂—Ph C₃ 1,4-piperazinylene 1-naphthyl 486. CH₂ NR¹ H C₃ 1,4-piperazinylene 2-OMe—Ph 487. CH₂ NR¹ H C₃ 1,4-piperazinylene 1-naphthyl 488. CH₂ NR¹ Me C₃ 1,4-piperazinylene 2-OMe—Ph 489. CH₂ NR¹ Me C₃ 1,4-piperazinylene 1-naphthyl 490. CH₂ NR¹ Boc C₃ 1,4-piperazinylene 2-OMe—Ph 491. CH₂ NR¹ Boc C₃ 1,4-piperazinylene 1-naphthyl 492. CH₂ NR¹ CH₃C═O C₃ 1,4-piperazinylene 2-OMe—Ph 493. CH₂ NR¹ CH₃C═O C₃ 1,4-piperazinylene 1-naphthyl 494. CH₂ NR¹ PhC═O C₃ 1,4-piperazinylene 2-OMe—Ph 495. CH₂ NR¹ PhC═O C₃ 1,4-piperazinylene 1-naphthyl 496. CH₂ NR¹ CH₂—Ph C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 497. CH₂ NR¹ H C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 498. CH₂ NR¹ Me C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 499. CH₂ NR¹ Boc C₂—N(Me)—C₂ 1,4-piperazinylene 1-naphthyl 500. CH₂ NR¹ CH₂—Ph CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 501. CH₂ NR¹ H CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 502. CH₂ NR¹ Me CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 503. CH₂ NR¹ Boc CH₂—C(CH₂)—CH₂ 1,4-piperazinylene 1-naphthyl 504. CH₂ NR¹ CH₂—Ph CH₂—CH(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 505. CH₂ NR¹ H CH₂—CH(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 506. CH₂ NR¹ Me CH₂—CH(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 507. CH₂ NR¹ Boc CH₂—CH(OH)—CH₂ 1,4-piperazinylene 1-naphthyl 508. CH₂ NR¹ CH₂—Ph CH₂—CH(CH₃)CH₂ 1,4-piperazinylene 1-naphthyl 509. CH₂ NR¹ H CH₂—CH(CH₃)CH₂ 1,4-piperazinylene 1-naphthyl 510. CH₂ NR¹ Me CH₂—CH(CH₃)CH₂ 1,4-piperazinylene 1-naphthyl 511. CH₂ NR¹ Boc CH₂—CH(CH₃)CH₂ 1,4-piperazinylene 1-naphthyl 512. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperidinylene 5-tetralinyl 513. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperidinylene 1-naphthyl 514. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperidinylene 2-OMe—Ph 515. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperidinylene 4-isoquinolinyl 516. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperidinylene 2-pyrimidinyl 517. CH₂ NR¹ CH₂—Ph C₂ 1,4-piperidinylene 2-OMe-naphthyl 518. CH₂ NR¹ H C₂ 1,4-piperidinylene 5-tetralinyl 519. CH₂ NR¹ H C₂ 1,4-piperidinylene 1-naphthyl 520. CH₂ NR¹ H C₂ 1,4-piperidinylene 2-OMe—Ph 521. CH₂ NR¹ H C₂ 1,4-piperidinylene 4-isoquinolinyl 522. CH₂ NR¹ H C₂ 1,4-pipendinylene 2-pyrimidinyl 523. CH₂ NR¹ H C₂ 1,4-piperidinylene 2-OMe-naphthyl 524. CH₂ NR¹ Me C₂ 1,4-piperidinylene 2-OMe—Ph 525. CH₂ NR¹ Me C₂ 1,4-piperidinylene 1-naphthyl 526. CH₂ NR¹ Me C₃ 1,4-piperidinylene 2-pyrimidinyl 527. CH₂ NR¹ CH₃—C═O C₂ 1,4-piperidinylene 2-OMe—Ph 528. CH₂ NR¹ CH₃—C═O C₂ 1,4-piperidinylene 1-naphthyl 529. CH₂ NR¹ Ph—C═O C₂ 1,4-piperidinylene 2-OMe—Ph 530. CH₂ NR¹ Ph—C═O C₂ 1,4-piperidinylene 1-naphthyl 531. CH₂ NR¹ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 5-tetralinyl 532. CH₂ NR¹ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 533. CH₂ NR¹ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe—Ph 534. CH₂ NR¹ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 4-isoquinolinyl 535. CH₂ NR¹ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-pyrimidinyl 536. CH₂ NR¹ CH₂—Ph C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 2-OMe-naphthyl 537. CH₂ NR¹ H C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 538. CH₂ NR¹ Me C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 539. CH₂ NR¹ Boc C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 540. CH₂ NR¹ CH₃—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 541. CH₂ NR¹ Ph—C═O C₂ 1,2,3,6-tetrahydro-1,4-pyridinylene 1-naphthyl 542. CH₂ NR¹ CH₂—Ph C₂ 1,4-homopiperazinylene 1-naphthyl 543. CH₂ NR¹ H C₂ 1,4-homopiperazinylene 1-naphthyl 544. CH₂ NR¹ Me C₂ 1,4-homopiperazinylene 1-naphthyl 545. CH₂ NR¹ Boc C₂ 1,4-homopiperazinylene 1-naphthyl 546. CH₂ NR¹ CH₂—Ph C₂ azepan 1-naphthyl 547. CH₂ NR¹ H C₂ azepan 1-naphthyl 548. CH₂ NR¹ Me C₂ azepan 1-naphthyl 549. CH₂ NR¹ Boc C₂ azepan 1-naphthyl 550. CH₂ NR¹ CH₂—Ph C₂ tetrahydro-2H-azepinylene 1-naphthyl 551. CH₂ NR¹ H C₂ tetrahydro-2H-azepinylene 1-naphthyl 552. CH₂ NR¹ Me C₂ tetrahydro-2H-azepinylene 1-naphthyl 553. CH₂ NR¹ Boc C₈ tetrahydro-2H-azepinylene 1-naphthyl 554. CH₂ NR¹ CH₂—Ph C₂ tetrahydro-2H-azepinylene 1-naphthyl 555. NR¹ CH₂ CH₂—Ph C₂ tetrahydro-2H-azepinylene 1-naphthyl 556. NR¹ CH₂ Me C₂ 1,4-piperazinylene 1-naphthyl 235° C. 557. NR¹ CH₂ CH₃—C═O C₂ 1,4-piperazinylene 1-naphthyl 236° C. 558. NR¹ CH₂ Ph—C═O C₂ 1,4-piperazinylene 1-naphthyl 245° C. 559. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 4-quinazolinyl 270° C. 560. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-quinazolinyl 260° C. 561. NR¹ CH₂ Boc C₂ 1,4-piperazinylene 4-isoquinolinyl 286° C. 562. NR¹ CH₂ H C₂ 1,4-piperazinylene 4-isoquinolinyl 290° C. 563. NR¹ CH₂ Ph—CH₂ C₄ 1,4-piperazinylene 2-pyrimidinyl 265° C. 564. NR¹ CH₂ Ph—CH₂ C₃ 1,4-piperazinylene 4-indanyl 281° C. 565. NR¹ CH₂ Ph—CH₂ C₂ 1,4-piperazinylene 2-Cl—Ph 225° C. 566. NR¹ CH₂ Ph—CH₂ C₂ 1,4-piperazinylene 2-pyrimidinyl 250° C. 

We claim:
 1. A compound of the formula I

where one of the two radicals X and Y is CH₂ and the other is NR¹, R¹ is hydrogen, (C₁₋₈) alkyl branched or unbranched, CO—(C₁₋₄)-alkyl, CO₂tBu, CO-aryl and a phenylalkyl-C₁-C₄ radical which in turn may be substituted on the aromatic system by F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, A is branched or unbranched (C₁₋₁₀)-alkylene or straight-chain or branched (C₂₋₁₀)-alkylene which comprises at least one group Z which is selected from O, S, NR², cyclopropyl, CO₂, CHOH, a double or triple bond, R² is hydrogen and C₁-C₄ alkyl, B is 1,4-piperidinylene, 1,2,3,6-tetrahydro-1,4-pyridinylene, 1,4-piperazinylene or the corresponding cyclic compounds enlarged by one methylene group, with the linkage to A being via an N atom of B, and Ar is phenyl which is unsubstituted or substituted by (C₁₋₆) alkyl branched or unbranched, O—(C₁₋₈)-alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR² ₂, CO₂R², cyano or phenyl, or is tetratinyl, indanyl, fused aromatic systems.
 2. A compound as defined in claim 1, where one of the two radicals X and Y is CH₂ and the other is NR¹, R¹ is hydrogen, (C₁₋₄) alkyl branched or unbranched, CO—(C₁₋₄)-alkyl, CO₂tBu, COPh or a phenylalkyl C₁-C₂ radical which in turn can be substituted on the aromatic system by F, Cl, Br, I, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, hydroxyl or cyano, A is (C₂₋₅) alkylene branched or unbranched or (C₂₋₅) alkylene which comprises a group Z which is selected from CHOH, cyclopropyl, a double or a triple bond, B is 1,4-piperidinylene, 1,2,3,6-tetrahydro-1,4-pyridinylene, 1,4-piperazinylene or homopiperazinylene, where the linkage to A takes place via an N atom of B, and Ar is phenyl which is unsubstituted or substituted by (C₁₋₆) alkyl branched or unbranched, O—(C₁₋₆)-alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, CO₂R², NR² ₂, cyano or phenyl, or is tetralinyl, indanyl, fused aromatic systems.
 3. A compound of the formula I as defined in claim 1, where one of the two radicals X and Y is CH₂ and the other is NR¹, R¹ is hydrogen, (C₁₋₂) alkyl, CO—(C₁₋₄)-alkyl or a phenylalkyl C₁-C₂ radical, A is (C₂₋₃) alkyl, B is 1,4-piperidinylene, 1,4-piperidinylene or 1,2,3,6-tetrahydro-1,4-pyridinylene and Ar is pyrimidinyl, phenyl which is unsubstituted or substituted by O(C₁₋₂) alkyl in the ortho position, tetralinyl, indanyl or naphthyl which is unsubstituted or substituted by (C₁₋₄) alkyl or O(C₁₋₂) alkyl.
 4. A compound of the formula I as claimed in claim 1, where Ar is naphthalene which is unsubstituted or substituted by (C₁₋₄) alkyl or O(C₁₋₄) alkyl, anthracene or 5- or 6-membered aromatic heterocycles having 1 or 2 heteroatoms which are selected, independently of one another, from O and N, which may be fused to other aromatic radicals, and their salts with physiologically tolerated acids.
 5. A compound as defined in claim 2, where Ar is naphthalene which is unsubstituted or substituted by (C₁₋₄) alkyl or O(C₁₋₄) alkyl, or 5- or 6-membered aromatic heterocycles having 1 or 2 nitrogen atoms, which may be fused to other aromatic radicals.
 6. A composition having a high affinity for 5-HT_(1B) and 5-HT_(1C) serotonin receptor which comprises a carrier or diluent and an effective amount of a compound as defined in claim
 1. 7. A method of treating depression in a patient in need thereof which comprises administering to said patient an effective amount of a composition as defined in claim
 6. 8. A method of selectively binding the receptors of 5-HT_(1B) or 5-HT_(1A) in a patient in need thereof which comprises administering to said patient an effective amount of a composition as defined in claim
 6. 9. The method of claim 8, where the selective serotonin antagonism is supplemented by inhibition of serotonin reuptake. 